The idea of applying oral contraceptives (OCs) for 21 days followed by a pill break of 7 days to allow withdrawal bleeding was based primarily on the desire to mimic the natural menstrual cycle resulting in 13 menstruations per year. A Dutch telephone survey (Contraception, 1999; 59:357-362) found that the majority of women would prefer either a decreased frequency of bleeding to less than once a month or complete elimination through the extended use of oral contraceptives. Additionally, the majority of women (80.5%) preferred to have either less painful, shorter or less heavy periods or even desired complete amenorrhea.
The first large study on a fixed extended oral contraceptive regimen (90 days=84 days of active pills followed by 6 hormone-free (placebo pills)) was published by Loudon and his colleagues in 1977 (British Medical Journal, 1977; 2:487-490). In this study a monophasic OC [50 μg Ethinyl estradiol (EE)/2.5 mg lynestrenol] was used. Breakthrough bleeding decreased with each three month cycle and no breakthrough bleeding was cited after 9 months of use. Intermenstrual bleeding accounted for 11% of the drop-outs from the study.
Seventeen years later a prospective study on continuous use of 30 μg EE+150 μg LNG (Nordette®) over 84 days followed by one week of placebo was published by Kovacs et al. (The British Journal of Family Planning, 1994; 19:274-275). Of the 203 women who entered the study only 59 (29.1%) completed 12 months of treatment (4×84+7 days). The most frequent reasons for discontinuation were breakthrough bleeding in 73 patients (50.7%) and breast tenderness and headaches in 31 patients (21.5%) each. The drop-out rate was highest during the first extended cycle (13 weeks) in which 34.5% (n=70) of the enrolled women were lost while the drop-out rate in the second to fourth extended cycle (26, 39+52 weeks) amounted to 21.8% (43), 12.3% (25) and 3.0% (6) respectively. The authors state that even though the ability to decrease the incidence of menstruation was appreciated by many women this was negated to some degree by the high incidence of breakthrough bleeding.
Hodgen disclosed a fixed regimen for oral contraceptive use which should maintain the efficacy while providing enhanced control of endometrial bleeding (U.S. Pat. No. 5,898,032). In addition to less menstrual bleeding and patient anemia, higher compliance rates and more lifestyle convenience for patients are listed as advantages of this method. According to the claims, a monophasic combination of an estrogen and progestin is continuously administered for 60-110 consecutive days followed by 3-10 days of no administration (fixed, predetermined duration). The claimed daily amounts of estrogen and progestin are equivalent to 5-35 μg EE and 0.025-10 mg of norethindrone acetate (NETA). Other progestins like levonorgestrel (LNG) or desogestrel are also described.
Hesch (U.S. Pat. No. 6,500,814) discloses a low dose fixed extended cycle product/regimen which according to the inventor surprisingly ensures high contraceptive reliability and prevents inter-menstrual bleeding. Additionally a reduction in OC related side effects (e.g. thrombosis) and a favorable effect on the pre-menstrual syndrome (PMS) are described. Furthermore prophylaxis and treatment of breast cancer are possible with the product according to the invention. Hesch claims continuous and uninterrupted administration of a combined hormonal contraceptive for a period of greater than 110 days. Various natural or synthetic estrogens and progestins are described. When EE is used its dosage is claimed to be between 1-20 μg/day.
Kulmann (WO 02/22110) discloses another process for hormonal contraception which reduces the number of withdrawal bleedings whilst ensuring reliable contraception. The process is characterized by a sequence of successive extended cycles (=“taking periods”) with increasing duration. Thus for example the patient may start with one taking period of 21 active tablets followed by 7 placebos (21/7) which is followed by a taking period of n×42/7. With the exception of the final taking period the duration of all prior periods is predetermined (fixed). According to the invention it is also possible to successively reduce the hormone dosage (various progestins and/or estrogens listed) between taking periods.
Sulak et al. (Am J Obstet Gynecol, 2002; 186:1142-1149) retrospectively studied the acceptance of extended cycle use in a larger number of patients with hormone withdrawal symptoms. The primary reasons for considering an extended OC regimen were: to decrease symptoms of headache (35%), dysmenorrhea (21%), hypermenorrhea (19%) and premenstrual symptoms (13%). Patients were allowed to alter their standard 21+7 regimen by extending a specific number of weeks such as 6, 9 or 12 or extending until breakthrough bleeding or spotting developed, stopping for 3-7 days and resuming. If they completed 12 weeks of active pills and wished to continue without a hormone-free break they were allowed to do so. There was no limit on the numbers of days a patient could extend. All patients were prior pill users taking monophasic pills with 30-35 μg ethinyl estradiol and one of the following progestins: norethindrone, levonorgestrel, norgestimate or desogestrel. Of the 267 patients who initiated the extended cycle regimen 57 (21%) chose to stop using OCs for various reasons like worsening in side effects including nausea, headache, acne, leg cramps, high blood pressure, yeast infections, breakthrough bleeding and PMS (24 patients) and a desire for pregnancy (13 patients). Of the 210 patients who continued to use OCs, 38 (18%) chose to return to the standard 21/7 regimen most commonly due to breakthrough bleeding (11 patients), breakthrough spotting (9) and heavy withdrawal bleeding (2 patients). The typical pattern of extended OC use by patients was 12±12 weeks (mean±SD) weeks of active pills with a median of 9 weeks and a range up to 104 weeks. The typical pill free interval was reported as 6±2 days with a median of 5 days and a range of 0-7 days.
Recently the results of a phase III multicenter 1-year trial on a fixed extended OC regimen with a 91-day cycle days versus a normal 28-day cycle (21 days active+7 placebo pills) have been published by Anderson et al. (Contraception, 2003; 68:89-96). The extended cycle regimen according to Hodgen (U.S. Pat. No. 5,898,032) was found to be effective in preventing pregnancy and had a safety profile comparable to the 28 day regimen (30 μg EE/150 μg LNG each). However, the extended cycle regimen patients reported a greater number of unscheduled (breakthrough) bleeding amounting to 37.6 days compared to 18.3 days for the 28-day regimen. The total days of bleeding unscheduled+scheduled (=menstrual bleeding) during the study year (364 days) were 48.2 days for the extended cycle compared to 50.8 days for the standard cycle. It was reported that for the extended cycle breakthrough bleeding (BTB) decreased with each successive cycle (84+7 each) from a median of 12 days during cycle 1 to a median of 4 days during cycle 4.
The most common reasons given for study discontinuation were bleeding, increased weight, mood swings and acne (=adverse events). Discontinuation due to unacceptable bleeding accounted for 7.7% of the 91-day regimen patients compared to 1.8% in the 28-day regimen group. The total drop out rates amounted to 40.6% and 28.8% respectively.
The product which was tested in this study has been launched in the US in September 2003 (Seasonale®, Barr Laboratories). In the product label it is stated that the patients on the 91-day treatment cycle should initially expect to have more bleeding or spotting between their menstrual periods than if they were taking a 28-day treatment cycle. Finally it is pointed out that intake of Seasonale® should not be stopped because of the bleeding.
In the Clinical Review of NDA 21-544 (Sep. 4, 2003) for Seasonale® additional results on Seasonale® Ultra-Lo (20 μg EE/100 μg LNG daily) are reported. It was observed that the fixed (84+7 days) extended regimen with a lower EE dose results in an even worse bleeding control. Thus the drop out rates for Seasonale® Ultra-Lo due to bleeding problems increased to 13.8% compared to 7.7% for Seasonale® (table 23). In comparison the drop out rate for the corresponding standard cycle (21+7 days) product Levlite® is reported to amount to only 0.9% in the same study.
Among the most frequently reported adverse events related to bleeding, menorrhagia was most often found. The respective values amount to: 11.6% for Seasonale®, 14.9% for Seasonale® Ultra-Lo and 2.6% for Levlite® (table 24). It has to be noted that the MedDRA term menorrhagia which was used for this study incorporates a number of adverse events related to vaginal bleeding such as intermittent, unexpected, breakthrough etc.
Similar observations can be drawn from the comparison between Loestrin 30 (30 μg EE/1.5 mg NETA) and Loestrin 20 (20 μg EE/1.0 mg NETA). Loestrin 30 is a widely used oral contraceptive which gives excellent cycle control. It is well known that Loestrin 30 is suitable for administration in an extended use regimen. Loestrin 20 gives very poor cycle control (Szarewski 1991, Szarewski & Guillebaud 1994, 1998, 2000, 2002, Wilkinson & Szarewski 2003) and therefore cannot be recommended for fixed extended use (Opposition proceedings against EP 0 911 029 B1, Declaration of Anne Szarewski, par. 9-11).
Spona et al. (U.S. Pat. No. RE37,564 E) teach a combination product for oral contraception comprising 23 or 24 dosage units each containing an estrogen (20 μg EE) and a progestin (2.5 to 3.0 mg drospirenone or 1 to 2 mg cyproterone acetate) and 5 or 4 blanks or placebos to complete the 28 days cycle. Such products result in a pronounced ovarian suppression without frequent follicular maturations.
Hodgen (U.S. Pat. No. 5,552,394) describes a method of female contraception which addresses the problem of increased bleeding problems for lower dose (estrogen+progestin) standard cycle (28-days regimen) OCs during the early months of use. Thus the overall instances of bleeding control problems for OCs have increased as the doses were reduced as reflected by the increase in breakthrough bleeding (untimely flow or spotting). By administering a monophasic combination of an estrogen and progestin for 23-25 consecutive days followed by a 2-5 day pill free period a reduced incidence of breakthrough bleeding could surprisingly be observed after the first 28-day cycle. The claimed daily amounts of estrogen and progestin are equivalent to about 1-35 μg EE and about 0.025-10 mg NETA, respectively, in which the weight ratio of estrogen to progestin is at least 1:45 calculated as EE to NETA. When other estrogens or progestins are used an adjustment in the used amounts based on the relative potencies should be made. Thus 3.5 mg of NETA are roughly equivalent to 1 mg of LNG or desogestrel or 0.7 mg of gestodene.
According to the prior art in the field of extended cycle regimens (see above) it was assumed that even for low dose (estrogen) hormonal contraceptives, stable extended cycles (i.e. absence of inter-menstrual bleeding) of fixed duration could be obtained and maintained even during the first year of administration. However, the published clinical data do not support these claims. Just to the contrary it was observed in large controlled clinical studies that administration of a low dosed estrogen composition (<30 μg EE) in a fixed extended cycle regimen leads to far higher bleeding complications and thus drop out rates in clinical practice compared to extended cycle regimens with higher EE dose (≧30 μg). Most notably the bleeding complications for fixed extended cycle regimens in general were found to be much higher than for the corresponding standard cycle (21+7 days) regimens.
In a recent review on the available compositions and methods for extended OC use by Henzl and Polan it was concluded that either alternative routes of application to the oral route or use of different hormonal agents than those used in the available products should be pursued to improve some of the deficiencies of the current schedule, breakthrough bleeding and spotting in particular (Journal of Reproductive Medicine 2004; 49:162-174).
Thus there is a clear need for an extended OC regimen which reduces or eliminates the bothersome intermenstrual bleeding (breakthrough bleeding and/or spotting) problems observed for fixed extended regimens. Such regimen would allow to comply with the desire of the majority of women who would prefer either a decreased frequency of menstrual bleeding to less than once a month or complete elimination through the extended use of oral contraceptives. There is still further need that such extended regimen should preferably be a low dosed (especially estrogen) regimen.
The low dose aspect is of special importance in such continuous administration regimens in order to minimize the total (annual) hormone exposure to compensate for the additional hormone administration due to the reduced number of hormone free phases compared to the standard cycle (21+7 days) regimen.
By allowing shorter pill breaks such an extended regimen should further minimize the intermenstrual and/or menstrual bleeding and additionally diminish disorders which occur during the hormone free intervall, as for instance symptoms related to PMS (premenstrual syndrome) incl. headaches, dysmenorrhea and pelvic pain, hypermenorrhea and acne (i.e. menstruation related disorders).
Furthermore such an extended OC regimen should offer flexibility regarding its duration to allow the patients to adapt the regimen (i.e. time and frequency of menstruation) to their specific biological/medical and individual needs.
Additionally such a flexible extended OC regimen should potentially allow a further reduction of estrogen and/or progestin dose compared to the available standard cycle products (e.g. 21+7 or 24+4 days).
Finally such a contraceptive regimen should offer additional therapeutic benefits (e.g. a positive influence on endometriosis, PMS, PMDD, polycystic ovarian syndrome (PCOS)) not directly related to bleeding disorders to the patients. Consequently such regimen should also be suitable for treatment of endometriosis, PMS, PMDD or polycystic ovarian syndrome (PCOS)